The aim of this project is to study carbohydrate structures in mucins and relate these to states of differentiation and malignant transformation in colonic epithelium. One arm of the study is designed to detect and develop markers of cellular differentiation, malignancy, and premalignant tissue. A second arm is designed to study the structural and enzymatic basis of the heterogeneity of colonic mucins. Differentiation-dependent changes have been found in the normal colon; transformation-associated changes have been found in cancer and "transitional mucosa." Identification of modifications in mucin structure has been found in a variety of premalignant epithelia, including adenomatous polyps, rectal biopsies from patients with chronic ulcerative colitis, and colons from mice treated with a chemical carcinogen. Preliminary evidence suggests that cancer-associated alterations in colonic mucins may be due to incomplete glycosylation of the oligosaccharide chains. In the past year, progress has been made in two areas. First, large quantities of mucin may be obtained through the generation of xenografts in nude mice from cultured human cancer cells. Intracellular mucin-type glycoconjugates may be identified in cultured cells, and secreted mucin has been identified and isolated from the xenografts. This will allow us to pursue a biochemical analysis of the immunochemical determinants of cancer-associated mucin. Secondly, colons from several species of marmosets (new world monkeys) have been examined and found to have carbohydrate structures similar to those in humans. In captivity, the cotton-top tamarin (Saginus oedipus oedipus) develops an illness similar to ulcerative colitis in humans, and colonic carcinoma complicates the illness in 25 to 50% of the animals. The cancer-associated mucin determinant was found in the colons of a large percentage of this and two other species of tamarins that develop colitis in captivity, and significantly larger amounts were found in the species in which cancer develops and in those colons in which a cancer was also present. Thus, we have new mechanisms to improve our study of both the molecular basis of this phenomenon and an interesting animal model of the colitis-cancer relationship. (1)